Mantle cell lymphoma associated sphingosine-1 phosphate inhibits natural killer T cell mediated antitumor responses (TUM2P.1042)

Abstract

Abstract The incidence of lymphoma in the US is rising. While chemoimmunotherapy causes remissions in mantle cell lymphoma (MCL), responses are not durable and most patients relapse. New strategies that focus on eliminating tumor-associated immunosuppressive factors are needed to improve patient outcomes. One of the earliest pathways to be activated during an immune response is CD1d-mediated presentation of lipid antigens to natural killer T (NKT) cells. We have found that MCL patients have a significant reduction in circulating NKT cell number and function. We hypothesized that MCL-associated sphingosine-1 phosphate (S1P) can down regulate CD1d-dependent NKT cell responses to MCL. We found that inhibition of S1P signaling in MCL cell lines led to increased CD1d-mediated NKT cell activation, as assessed by cytokine production and cytotoxicity. Furthermore, knockdown of sphingosine kinase 1 in MCL cell lines resulted in the presentation of an activating endogenous antigen. These results demonstrate that S1P regulates CD1d-mediated antigen processing and presentation to NKT cells by altering the endogenous repertoire of lipid antigens and suggest that targeting this pathway could be an important immunotherapeutic strategy.